HCV is a small enveloped Flaviviridae family virus with a 9.6-kb single, positive-stranded RNA genome consisting of a 5′ untranslated region (UTR), a large open reading frame encoding the virus-specific proteins, and a 3′ UTR. The 5′ UTR contains an internal ribosome entry site (IRES) that mediates translation of a single polyprotein of approximately 3000 amino acids. The polyprotein consists of structural proteins (core, E1, and E2) located in the N terminus, followed by p7 and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) encoded in the remainder.
While there is a recognized need for an effective HCV vaccine, selection of the viral strain to be used as an antigen has been arbitrary. Studies in humans and chimpanzees have shown that the host immune system is able to launch an effective response to HCV, and people who have cleared infection once are likely to do so again, though this effect is potentially attributable to host genetics. The genetic diversity of HCV, which is even greater than that of HIV, poses a great challenge to the development of an effective vaccine. Selection of an appropriate strain as a vaccine candidate is crucial since even a single amino acid substitution could reduce vaccine effectiveness by eliminating recognition by T cells specific for that epitope. Use of an ancestral or consensus sequence as a vaccine candidate has been proposed for HIV-1. Compared to a consensus sequence, a mosaic approach (including multiple variant sequences of individual epitopes) generated more vigorous T cell responses to HIV-1 epitopes. Mosaic candidates have recently been identified for HCV although their effectiveness is still unknown.
Hepatitis C virus (HCV) affects approximately 170 million people worldwide. Approximately 20-25% of patients with acute hepatitis C achieve spontaneous clearance of the virus but 75%-80% develop chronic infection. Approximately 20% of chronic hepatitis C patients develop cirrhosis and of these, 4% will develop hepatocellular carcinoma and 6% will develop end stage liver disease. There is no available HCV vaccine and commonly used interferon-based treatment is toxic, prolonged, expensive, not consistently successful, and not effective in the most advanced forms of disease.
As such, there still exists an unmet need for more effective tools for preparing antigens, antibodies and vaccines against HCV and related viruses.